On July 11, 2013 a paper was published online by Brasky et al. in the Journal of the National Cancer Institute entitled, “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial.” The authors found that higher plasma omega-3 fatty acid levels were associated with increased risk for developing prostate cancer. In this study, plasma phospholipid omega-3 levels were measured in 834 men who eventually developed prostate cancer (the time between plasma sampling and diagnosis is not available from the abstract), and 1393 men who did not. Using standard statistical methods, they found that men in the highest quartile of omega-3 had a 43% to 71% increased risk for prostate cancer (depending on severity). This is the same conclusion that the same group reached in 2011 in a study in another cohort entitled, “Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial.”(1) So with two studies reaching the same conclusion, it is important to seriously consider its findings.

I will be the first to admit that had this study turned out the “right” way, I would have embraced its findings and had no criticism of its design or methods. It is disingenuous, therefore, for me to find fault with the way the study was conducted just because I don’t agree with the findings. Nevertheless, we should examine the methods to be clear on the context of the conclusions.

First, the reported EPA+DHA level in the plasma phospholipids in this study was 3.62% in the no-cancer control group, 3.66% in the total cancer group, 3.67% in the low grade cancer group, and 3.74% in the high-grade group. These differences between cases and controls are very small and would have no meaning clinically as they are within the normal variation. Based on experiments in our lab, the lowest quartile would correspond to an HS-Omega-3 Index of <3.16% and the highest to an Index of >4.77%). These values are obviously low, and virtually none of the subjects were in “danger” of having an HS-Omega-3 Index of >8%. In Framingham, the mean Omega-3 Index of participants who were not taking fish oil supplements was 5.2% and for those taking supplements, it was 7.5%.(2) Both of these numbers are considerably higher than the values reported by Braskey et al., even in their highest quartile. Thus, it is extremely unlikely that these patients were taking fish oil supplements. Indeed, the SELECT study (in which all these patients were participants) was a randomized trial of vitamin E and selenium supplements for the prevention of prostate cancer. In the study protocol, it is stipulated that if the subjects wanted to take a multi-vitamin, the study would provide it; nothing is said about fish oil supplements, but it is hard to imagine their use was widespread in this trial.

So to conclude that regular consumption of 2 oily fish meals a week or taking fish oil supplements (both of which would result in an Index above the observed range) would increase risk for prostate cancer is extrapolating far beyond the data. This study did not test the question of whether giving fish oil supplements (or eating more oily fish) increased prostate cancer risk; it looked only a blood levels of omega-3 which are determined by intake, other dietary factors, metabolism, and genetics. The endless repetition of “supplements are dangerous” in the news media is not based on any data from this study.

But even granting that the associations they reported are real, the findings of this study do not mean that EPA and DHA play any role in the development of prostate cancer. Associations do not imply causation. For example, it is possible that some component of whatever fish these patients were consuming was carcinogenic, in which case the serum omega-3 levels were just a marker of fish (i.e., carcinogen) intake.

It is important to put these findings into perspective (which the authors failed to do). First consider the risk of dying from prostate cancer vs. ischemic heart disease (IHD). Based on the National Vital Statistics Report for deaths in the US in males in 2010, (http://www.cdc.gov/nchs/data/dvs/deaths_2010_release.pdf), there were about 28,500 deaths from prostate cancer and 207,500 deaths from IHD: a 7.3x higher rate of death for heart disease. If one assumes (conservatively) that higher fish intake reduces risk for death from heart disease by only 10%, and (liberally) increases risk for death from prostate cancer by 50%, then the chances of dying from coronary heart disease (CHD) are still 4.4x higher than from prostate cancer. This very crude analysis suggests that even in the worst case scenario, the benefit of higher omega-3 intakes/levels still outweighs the risk.

The authors also failed to present the fuller story taught by the literature. The same team reported in 2010 that the use of fish oil supplements was not associated with any increased risk for prostate cancer.(3)A 2010 meta-analysis of fish consumption and prostate cancer reported a reduction in late stage or fatal cancer among cohort studies, but no overall relationship between prostate cancer and fish intake.(4) Terry et al. in 2001 reported higher fish intake was associated with lower risk for prostate cancer incidence and death,(5) and Leitzmann et al. in 2004 reported similar findings.(6) Higher intakes of canned, preserved fish were reported to be associated with reduced risk for prostate cancer.(7) Epstein et al. found that a higher omega-3 fatty acid intake predicted better survival for men who already had prostate cancer,(8) and increased fish intake was associated with a 63% reduction in risk for aggressive prostate cancer in a case-control study by Fradet et al..(9) So there is considerable evidence actually FAVORING an increase in fish intake for prostate cancer risk reduction.

Another piece of the picture is to compare prostate cancer rates in Japan vs. the US. Here is a quote from the World Foundation of Urology*:

Since the Japanese typically eat about 8x more omega-3 fatty acids than Americans do and their blood levels are twice as high, you’d think their prostate cancer risk would be much higher… but the opposite is the case.

There is also a wealth of evidence from randomized clinical trials with fish oils in which the incidence of cancer (rarely subsetted) is always tracked as a possible adverse event. The table below shows the findings for the 8 major studies reported to date which included over 78,000 patients. In none of these studies was cancer incidence significantly increased by omega-3 fatty acid supplementation.

In summary, the work of Brasky et al. does add to the evidence-base for omega-3 fatty acids and prostate cancer, which taken as a whole (not even getting into animal studies which are typically positive) support a neutral, if not beneficial, effect of fish oil in prostate cancer. The RCT data do not support an effect of omega-3 on cancer risk in general, and a 2012 review of omega-3 and prostate cancer concluded, “Thus, epidemiological studies provide inconsistent results, suggesting an inverse association of LC n-3 PUFA.”(18)

There will always be mixed findings in studies of “diet” and “disease” since both predictor and outcome entail so many variables, known and unknown. Higher omega-3 levels are associated with lower rates of death from any cause,19,20 from sudden cardiac arrest,21 and with slower rates of cellular aging.22 The risk benefit for fish oils remains very favorable. Read More…

Omega-3 fatty acids are essential fatty acids in the human diet that are primarily found in oily fish like salmon, sardines, albacore tuna, herring, mackerel, etc. They are also available in fish oil soft gels. The principle omega-3 fatty acids are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Over the last 25 years, compelling evidence has accumulated from epidemiological studies and large clinical trials demonstrating their beneficial impact on joint, brain, eye, and heart function. With regard to the cardioprotective effects of omega-3 oils, the strongest evidence to date relates to reducing risk for sudden cardiac death, the primary cause of coronary heart disease (CHD) death in the US today.

The American Heart Association reports that CHD is the number one killer of American men and women, accounting for more than one of every five deaths in the United States, usually as sudden death from cardiac arrest. Recognizing the cardioprotective effects of omega-3s, the American Heart Association (AHA) recommends that patients with documented CHD should consume about 1,000 mg of omega-3s (specifically, combined DHA+EPA) per day; those without documented CHD should eat a variety of fish, preferably oily, at least twice a week, to provide about 500 mg of EPA+DHA per day. It is very difficult, however, to reliably estimate omega-3 consumption based upon fatty fish intake because DHA and EPA vary greatly with species, season, maturity, fish’s diet, post-catch processing, and cooking methods. A high-quality, highly purified fish oil supplement can deliver a more precise amount of omega-3s. Even then, individual differences in absorption, metabolism, and distribution can lead to variable responses to a given intake.

So how do you know if you are getting enough omega-3s?

Now there is a blood test —the HS-Omega-3 Index™— that can measure your levels of the cardioprotective omega-3 fatty acids, DHA and EPA. Researchers have discovered that one of the best risk indicators for sudden cardiac death is the level of omega-3 fatty acids (EPA and DHA) found in red blood cell membranes. The HS-Omega-3 Index test measures levels of DHA + EPA in the phospholipids of red blood cell membranes and is expressed as a percent of total fatty acids in the membrane. The result is a simple modifiable marker for the risk of death from coronary heart disease.

The target HS-Omega-3 Index is 8% and above, a level that current research indicates is associated with the lowest risk for death from CHD. On the other hand, an Index of 4% or less (which is common in the US) indicates the highest risk. Low levels are easily corrected through dietary changes or supplements and can quickly improve test results. Of course, this is just one of a number of risk factors that plays a role in CHD. Risks associated with other factors such as cholesterol, blood pressure, diabetes, family history of CHD, smoking, or other cardiac conditions are completely independent of and not influenced by omega-3 fatty acids. Any and all modifiable risk factors – including the HS-Omega-3 Index—should be addressed as part of any global risk reduction strategy.

A disclaimer should accompany every scientific article, “Read and Believe with Caution”. To say that weekly there is a study contradicting a prior clinical trial is probably an underestimation of the state of medical/scientific affairs. Hundreds of peer-reviewed journals now cross our desks and computer screens. How do we, the doctors and scientists, assimilate all these data? This is particularly difficult when one considers the complexity of statistical analyses that must be thrashed through in order to do justice to any single study. And then one must remember that we do not have every hour of every waking day to analyze trials. The result is far too often a leap to erroneous but easy conclusions. We saw this recently with a JAMA meta-analysis regarding fish oils (see the blog of my letter to JAMA) wherein standard statistical analysis was plainly deviated from. The result, an unfounded conclusion that no one on TV every mentioned. Perhaps they did not have the preparatory time necessary to dissect the statistics. Whatever the case, medical and lay opinions were unfairly and wrongly influenced by this trial.

And now we have another interesting study, this time in favor of supplements. On October 17th JAMA published on-line the results of a multivitamin analysis of Harvard’s famed Physicians’ Health Study. This trial revealed that simple (low dose) multivitamins could decrease cancer rates in men. Prior studies using high dose supplements have failed to demonstrate this. At the risk of being self-serving, over ten years ago I performed a small clinical trial (published in JANA – the Journal of the American Nutraceutical Association) demonstrating the possible downside of high-dose supplements. I responded to my own trial by forming a very conservative supplement company, VitalRemedyMD. And my first products were two simple daily multiples with no more than 100% of the RDV of the essential vitamins and minerals (the Daily2Tab and DailyMultiple – innovative names, I know). No more than that. I based these formulations more upon my review of basic science literature, than our too-highly-revered RCT (Randomized Clinical Trials). A decade later, the clinical trial is “catching up” with something that science had already taught us. My point here is that we in the medical world have shunned our roots, basic science. And, we have cut ourselves off from our mentors, the basic scientists. In fact, just last week an article I wrote on this subject that was published online – A Survey of Internists and Cardiologists: Are Discoveries in Fatty Acids Truly being translated into Clinical Practice? Prostaglandins, Leukotrienes and Essential Fatty Acids (available online 25 October 2012). It tells this story. There is a disconnect between science and medicine. It is real, prevalent, and very disturbing. It undermines our ability to grow and limits our capacity to cure. The only way I see we can conquer this impediment is by opening a continual and non-confrontational dialogue among the diverse elements of science and medicine. Only then can we have true translational medicine, the application of what is learned in the lab to the patient in our offices or hospital wards. Short of dialogue we will continue to exist in a modern tower of babble, and we all know how well that worked out.